Microsomal formation of a pyrrolic alcohol glutathione conjugate of clivorine. Firm evidence for the formation of a pyrrolic metabolite of an otonecine-type pyrrolizidine alkaloid.
The formation of the pyrrolic alcohol glutathione (GSH) conjugates of two different types of pyrrolizidine alkaloids (PAs), i.e. clivorine (an otonecine-type PA) and retrorsine (a retronecine-type PA), was investigated with rat microsomes in the presence of GSH. Two GSH conjugates identified as metabolites of retrorsine were the pyrrolic alcohol conjugated with one [7-GSH-dehydroretronecine (DHP)] or two (7,9-diGSH-DHP) molecules of GSH. diGSH-DHP, the less abundant of the two conjugates, had not been previously identified as a metabolite of PAs. In the case of clivorine, 7-GSH-DHP was identified. This is the first unequivocal identification of a pyrrolic metabolite of an otonecine-type PA. Consequently, this study provides the strongest evidence obtained to date to support the hypothesis, suggested >25 years ago, that the mechanism of hepatotoxicity induced by otonecine-type PAs involves key metabolic steps similar to those for retronecine-type PAs.
Lin
G
G
Department of Pharmacology, The Chinese University of Hong Kong, Shatin, Hong Kong.
Cui
Y Y
YY
Hawes
E M
EM
D000438:Alcohols / Q000032:analysis / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D011758:Pyrroles / Q000032:analysis / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D000438:Alcohols; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; D005978:Glutathione; C028677:clivorine; C003300:retrorsine